Although a variety of delivery systems are being developed for different routes of administration like the oral, parenteral, nasal and transdermal, the oral route remains attractive for drug delivery because this mode of administration is an easy, convenient, noninvasive and familiar method of drug delivery. The majority of prescribed drugs are designed for oral application since they can be self-administered by the patient without hospitalization. Oral dosage forms are designed according to the nature of the drug, the nature of application and the need for any special effects. The common oral dosage forms include: liquid mixtures like solutions, suspensions, solid dosage forms like tablets and capsules and liquid filled capsules etc. The solid dosage forms are further modified depending on the therapeutic action desired, like controlled, extended or delayed release. However, patients at the extremes of age, such as children and the elderly, often experience difficulty in swallowing solid oral dosages forms. For these patients the drugs are mostly provided in liquid dosage forms such as solutions, emulsions and suspensions. These dosage forms usually lead to perceptible exposure of the active drug ingredient to the taste buds, which is a very serious problem when the drug has an extremely unpleasant or bitter taste.
The bitter taste of the drugs, which are orally administered, is disadvantageous in several aspects. Taste is an important parameter governing the compliance. The disagreeable taste of drugs causes difficulties in swallowing or causes patients to avoid their medication thereby resulting in low compliance of patients. Conventional taste masking techniques such as use of sweeteners, amino acids, flavoring agents are often unsuccessful in masking the taste of the highly bitter drugs like quinine, barberin, etoricoxib, antibiotics like levofloxacin, ofloxacin, sparfloxacin, ciprofloxacin, cefuroxime axetil, erythromycin and clarithromycin. Thus taste-masking technologies are considered important and developed by many researchers.
Taste masking is a major problem when the drugs are extremely unpleasant and bitter and this problem is not restricted to the liquid oral compositions like solutions, dry syrup and suspensions but may also be encountered during the formulation of chewable tablets or dispersible tablets wherein these dosage forms usually lead to perceptible exposure of active ingredient to taste buds. Depending on the type of dosage form, various methods have been employed to overcome the unpleasant taste and bitterness of the drug.
Many polymers are employed for the taste masking of drugs. These polymers include the use of the cellulose derivatives like cellulose esters either enteric or nonenteric and cellulose ethers. The examples of the nonenteric cellulose esters include the cellulose acetate, cellulose triacetate, cellulose acetate butyrate and cellulose propionate. The enteric cellulose esters include cellulose acetate phthalate and hydroxy propyl methylcellulose phthalate. The cellulose ethers available are methylcellulose, ethyl cellulose, hydroxy ethyl cellulose, hydroxy propyl cellulose and hydroxy propyl methylcellulose. The Surelease by Dow Chemicals, and Aquacoats of FMC containing the ethylcellulose are most widely used.
A variety of polymethacrylates and acrylic polymers are available under the trade name Eudragit from Rohm Pharma. The acrylic polymers commonly employed are copolymers of methacrylic acid.
Various methods for taste masking have been tried earlier, which include use of ion exchange resins, complexation of bitter drugs with pharmaceutically acceptable excipients and coating of drugs by lipids and various polymeric materials. Of these, the coating is the most widely used technique for taste masking. Coating of the active ingredient can be done by any of the techniques known in the art like microencapsulation, hot melt granulation, Fluid bed coating, and spray drying.
European Patent EP 1219291 discloses chewable tablets and texture masked particles of the active ingredient, acetaminophen which is coated by a taste masking polymer ethyl cellulose and a film forming polymer and a texture masking coating solution of hydroxypropyl methyl cellulose and polyethylene glycol 800 and acesulfame potassium.
In another patent application JP 2002363066 the taste masked pharmaceutical or food composition is disclosed which is suitable for formulation as granule, tablet or a chewable tablet. The taste masked fine granule is obtained by using polymers such as ethyl cellulose, hydroxy propyl cellulose.
European patent EP 1166777 discloses yet another chewable tablet made from taste-masked particles. The active ingredient ibuprofen, was coated by the enteric polymer HPMCP and an insoluble film forming agent cellulose acetate and the chewable tablets which suppress throat burn were prepared from the coated particles by blending with aspartame, acesulfame potassium, citric acid, granular mannitol, fumaric acid, microcrystalline cellulose, and flavor.
Taste masking techniques are extended to the dispersible dosage forms and rapidly disintegrating tablets, too. The patent application WO 01/58449 discloses the water dispersible powder and tablets of paroxetine for the immediate release of the drug and a taste-masking agent comprising of the methacrylic acid copolymer. The taste-masked composition was obtained by spray drying of paroxetine and the polymer.
Patent Application WO 01/52848 discloses a taste masked oral formulation of linezolid which can be formulated as a suspension, a fast-disintegrating, effervescent or chewable tablet, by microencapsulating the antibiotic by solvent coacervation of ethyl cellulose with an optional seal coat of shellac and further coating the particles by functional polymer Eudragit L30 D. The formulated microcapsules can be suspended in an aqueous medium prior to oral administration to pediatric and geriatric patients, who are unwilling and/or find it difficult to swallow the tablets, else, fast-disintegrating tablets can be formulated which rapidly disperse into taste masked granules in the mouth.
The U.S. Pat. No. 6,663,893 discloses a taste masked drug with the coating composition comprising of dimethylaminoethyl methacrylate and neutral methacrylic acid ester, a cellulose ester polymer, and an alkaline modifier. The coating composition has a blend of polymer and an alkaline modifier where the alkaline modifier is added in an amount sufficient to increase the coating composition's dissolution rate in the stomach.
U.S. Pat. No. 6,001,392 discloses a controlled release syrup suspension for the oral administration containing dextromethorphan adsorbed on to a polystyrene sulfonate ion exchange resin. The drug polymer complex is coated by a mixture of ethyl cellulose or ethyl cellulose latexes with plasticizers and water dispersible polymers such as SURELEASE. For the drugs where immediate release is required for rapid action, the controlled release of the active ingredient may not be favored and a delay in release may also be of concern for drugs having a limited absorption window.
The patent application JP 2004010611 discloses the taste masking of drugs using composition of polymer containing calcium silicate, hydroxypropyl methyl cellulose acetate succinate and ethyl acrylate-methyl methacrylate copolymer.
The patent application US20040030033 discloses a film coating composition containing an acrylic polymer, a vinyl acetate polymer and a water-containing liquid. The film coat disclosed is suitable to provide modified release in pharmaceutical formulations.
The taste masked dosage forms consisting of the one or more cationic polymers synthesized from the dimethylaminoethyl methacrylate and neutral methacrylic acid esters like Eudragit E 100 and Eudragit E PO having the drug to polymer ratio less than one to two is disclosed in the patent application WO 2004022037.
Complexation is yet another method for taste masking of bitter drugs. U.S. Pat. No. 4,808,411 discloses a taste masked composition comprising 75-95% of erythromycin and about 5 to 75% of carbomer where the drug and carbomer are held together by ionic interactions between erythromycin and carbomer. The complex is further coated with a functional polymer, hydroxy propyl methylcellulose phthalate to make the preparation palatable. Erythromycin is released slowly from the complex to avoid a significant perception of bitterness in the mouth. It is clear that slow release, not fast release of bitter medicament is critical as disclosed in the patent. But complexing alone is not sufficient enough to mask taste. Coating with functional polymers is required to attain desired palatability and further proper selection of complexing agent is vital since drug release should not be compromised.
Patent Application WO 02/092106 discloses a taste-masked composition comprising polycarbophil and a macrolide antibiotic, clarithromycin. The complex is further coated with an acid resistant polymer Eudragit L100 55, releasing the drug in the intestine. For certain drugs the bioavailability may not be altered by the use of enteric coating where the drug is released in the small intestine, but for the drugs with a narrow absorption window restricted to the upper gastric region, the use of enteric coating may alter the bioavailability.
European Patent Application EP 0409254 discloses an oral particulate preparation with unpleasant taste being masked using ethyl cellulose and a water-swelling agent where the active is released rapidly from the said formulation.
U.S. Pat. No. 5,635,200 discloses a taste-masked preparation of bitter drug ranitidine by a lipid coating and dispersion of these coated particles in the non-aqueous medium. U.S. Patent Application 2003-028025 discloses taste-masked composition of gatifloxacin suitable for use in oral dosage forms, particularly for pediatric formulations. A crystalline co-precipitate of gatifloxacin and one or both of stearic acid and palmitic acid is used to effectively mask the bitter taste of gatifloxacin in the mouth and in aqueous suspension through a fill dosage cycle of fourteen days.
Patent Application WO 02/72111 discloses a taste masked pharmaceutical suspension of telithromycin. Four different coating agents Novata AB, Eudragit E100, glycerol monostearate and talc M10 are employed and at least three successive layers of coating are essential to taste mask telithromycin. The coated granules as disclosed could further be formulated as dry syrup, which is reconstituted as a suspension.
U.S. Pat. No. 4,865,851 discloses yet another method for taste masking highly bitter 1 acetoxy ethyl ester of cefuroxime in particulate form being coated with an integral coating of lipid at a mixture of lipids, which serves to mask the taste.
U.S. Pat. No. 5,286,489 describes a porous drug polymer matrix formed by admixing a bitter tasting active ingredient and a methacrylic ester copolymer in at least a 1:1 weight ratio of active ingredient to copolymer, effective to mask the taste of the drug. None of the examples described in the patent disclose the effect of these polymers on the release of the drug from the matrix. It is observed that the drug release is retarded from the matrix described herein.
Patent Application WO 00/56266 discloses the use of a high viscosity swellable polymer carbomer, in combination with film forming polymethacrylates and channelising agents for taste masking of bitter drugs. The addition of the water swellable polymer aids in the fast release of the active ingredient in the gastric media.
In yet another Patent application WO 00/76479 a taste masking composition, using a combination of two enteric polymers comprising methacrylic acid copolymer and a phthalate polymer is disclosed. The patent discloses the use of the channelising agents, which comprise the water-soluble or water swellable materials to aid the release of the active ingredient. The enteric polymers as disclosed in the patent are known to release the active ingredient in the alkaline pH where the polymers are soluble. Release of active ingredient will be delayed due to the use of the enteric polymers and in case of the medicaments having a narrow absorption window restricted to upper gastrointestinal tract, such system would be of limited use.
The taste masking formulations should be so designed that the bioavailability of the drugs is not compromised and the use of certain polymers like the enteric coatings should not affect the time to peak. Further the drug should be sufficiently absorbed to ensure effective therapeutic concentration in the plasma. Vogelman et al (B. Vogelman, William A. Craig Journal of Pediatric 1986, 108 (5, pt2) 835-40, & B. Vogelman, William A. Craig, S. Ebert, S. Gudmundsson, J. Leggett, Journal of Infectious Diseases 1988, 158(4), 831-47) have established that bactericidal killing is rapid, intensive and increases proportionately to the concentration. In the presence of high concentration of the drug, the killing is complete and almost instantaneous. In some drugs rapid and complete absorption and high systemic concentration are important to elicit the desired therapeutic effect.
Patent Application WO 02/43707 discloses oral pharmaceutical formulations for cefuroxime axetil in tablet form such that the cefuroxime axetil is contained in the tablet core, coated with double layered film coat of hydroxypropyl methyl cellulose and shellac. The first film coat as disclosed, serves to mask bitter taste of cefuroxime axetil and second film coat serves to delay the rupture time beyond 40 seconds. Since cefuroxime axetil is associated with gelling tendency in contact with aqueous media thereby reducing bioavailability, the rapid release of cefuroxime axetil from the core of the dosage form is more desirable.
U.S. Pat. No. 5,599,556, discloses liquid formulations where the active ingredient is coated with single outer polymeric coating derived from prolamine cereal grain proteins and plasticizing agent. The bitter drug clarithromycin comixed with polyvinyl pyrrolidone is coated by prolamine to achieve taste masking and the coated particulate matter is dispersed in a suspending medium of pH greater than 6. The coatings are designed to rapidly degrade once the composition leaves the mouth and reaches the stomach.
U.S. Pat. No. 548,436 discloses chewable tablets made from a coated medicament where the coating is designed to be soluble at the lower pH of the stomach but relatively water insoluble at the higher pH of the mouth. The coatings comprise a polymer blend of dimethylamiaoethyl methacrylate and neutral methacrylic acid ester and a cellulose ester. The above mentioned “reverse enteric” coating method of taste masking oral formulation is disclosed in connection with chewable tablets.
Patent Application WO 02/096392 discloses taste masking of highly water soluble drug cetrizine hydrochloride. The polymers like hydroxy propyl methyl cellulose, polyvinyl pyrrolidone, ethyl cellulose are used which effectively mask the taste of cetrizine in tablet form and release the drug immediately under the acidic conditions prevalent in stomach.
It is evident from the above disclosures, that taste masking can be achieved by various methods. Many natural and synthetic polymers, resins and waxes alone or in combination have been employed for taste masking. Whilst the use of polymer coats as mentioned in the above examples may be effective for taste masking, they retard dissolution of the drug. It is understood that there is a need for the development of such coating compositions, which are suitable for the application in the solid dosage forms and also the liquid orals. The maintenance of palatability of the formulations in the liquid dosage forms is more critical as here the possibility of the leaching of the drug in the surrounding media is more. A higher amount of the polymers may be required to achieve this. However as the amount of the enteric or the pH independent polymers like the ethyl cellulose is increased, there is a possibility of the retardation of the drug release. Hence there is a need to design the polymeric coating compositions, which are effective in taste masking, retarding the drug release in the aqueous media and yet releasing substantial amount of the drug without delay. The coating compositions should be such that they release the drug almost completely from the dosage form without affecting its absorption and bioavailability.
The present invention addresses this problem by incorporation of an acid soluble polymer in combination with other polymers, either pH independent or pH dependent with a specific dissolution window in the acidic pH<3.
The polymeric coating compositions disclosed it the present invention employing the combination of the pH dependent polymer like the acid soluble and the enteric polymer have the advantage that they would ensure complete release of the drug due to the presence of the acid soluble part and could be reconstituted in the pH range 3.5-5. Further the coating composition employing the acid soluble polymer and the pH independent polymers will have the advantage of the broader reconstitution pH range of 3.5 and above and yet the drug being released without much delay due to the solubilisation of the acid soluble polymer in the stomach. Further advantage is that when the polymer blends are used the total quantity of the polymer can be increased for better taste masking effect making optimal use of the properties of individual polymers constituting the blend without compromising the release.